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Archived Research Updates

2009 Research

December 11. 2009

Few Benefits Seen With Androgen Reduction for Spinal and Bulbar Muscular Atrophy

BALTIMORE (EGMN) –Long-term dutasteride therapy in men with spinal and bulbar muscular atrophy does not appear to improve muscle strength or fatigue and might actually lower mental quality of life, according to the results of a phase II, randomized, double-blind, placebo-controlled trial.

Patients derived some benefit from treatment with the 5-alpha reductase inhibitor, which converts testosterone into more potent dihydrotestosterone, as a result of a significant reduction in their number of falls and improvement in their physical quality of life.

Spinal and bulbar muscular atrophy (SBMA) is characterized by a toxic buildup of mutant androgen receptors with an excessively long string of glutamine residues in motor neurons. This buildup weakens bulbar and extremity muscles, causing difficulty with gait and dysphagia, and also might lead to gynecomastia, infertility, and other manifestations of androgen insensitivity. Dutasteride has been thought to be a potential therapy for SBMA because experiments in mice that were bred to express the mutant androgen receptor showed that reducing androgen levels could mitigate the toxicity of the mutant phenotype.

To evaluate the efficacy and safety of dutasteride, Dr. Kenneth H. Fischbeck, chief of the Neurogenetics Branch of the U.S. National Institute of Neurological Diseases and Stroke (NINDS) and his colleagues randomized 50 men with SBMA to either 0.5 mg/day of dutasteride or placebo. That dose of dutasteride is the same as that approved for treating symptomatic benign prostatic hyperplasia.

The men in each group were an average age of about 53 years, and had an average CAG repeat length of 4 codons (compared with wild-type human repeat length of 36 codons or less, a mean duration of weakness of about 12 years, and an average body mass index of about 28 kg/m2.

After 2 years, patients treated with dutasteride had virtually no appreciable increase in weight-scaled quantitative muscle assessment scores from baseline – the primary efficacy measure – whereas the scores in patients taking placebo declined by 5% from baseline. This difference was not significant, according to the investigators, who reported their results in a poster session at the annual meeting of the American Neurological Association.

On the Short Form-36 quality of life questionnaire (version 2), the physical component summary improved by about 14% from baseline for dutasteride-treated patients, which was significantly different from the 10% drop recorded in placebo-treated patients.

Significantly fewer falls occurred among patients who were treated with dutasteride than among those who received placebo (9 patients reporting 40 falls vs. 16 subjects reporting 63 falls).

However, patients who took dutasteride fared more poorly than those who took placebo on the mental component summary of the questionnaire, in which patients on placebo had a 10% improvement and patients on dutasteride worsened by about 7%.

Modified barium swallow scores, a measurement for dysphagia severity, worsened by a similar amount in subsets of patients from both arms.

Dutasteride did not have an effect on total and free testosterone levels after 2 years, but dihydrotestosterone levels declined during that period from 46 ng/dL at baseline to 5 ng/dL.

A total of two patients in the placebo arm and two in the dutasteride arm dropped out of the trial before the 2-year end point. One death in the dutasteride arm was caused by a cardiac event (confirmed by autopsy). One patient on dutasteride left the trial because of respiratory distress.

The muscle strength of men who were taking placebo declined by only 2% per year. “With such slow progression, longer trial duration or a more sensitive outcome measure may be needed to show therapeutic benefit,” the investigators wrote on their poster.

They also suggested that in future trials, it might be useful to conduct functional muscle testing with the Adult Myopathy Assessment Tool, which registered nearly a 5% rate of decline in placebo-treated patients, and other testing methods, such as physical quality of life and electrophysiological measures.

The trial was funded by the NINDS. None of the investigators had relevant disclosures.

From the Neuromuscular Research Unit, Department of Neurology and Copenhagen Muscle Research Center (N.P., G.A., F.T., T.D.J., J.V.), Department of Clinical Neurophysiology (C.C.), and Department of Clinical Genetics (F.W.), University of Copenhagen, Rigshospitalet, Denmark.

Objective: We examined the effect of aerobic exercise in patients with spinal and bulbar muscular atrophy (SBMA). SBMA is caused by a defect androgen receptor. This defect causes motor neuron death, but considering the important function of androgens in muscle, it is possible that muscle damage in SBMA also occurs independently of motor neuron damage.

Results: Wmax increased by 18%, and CS activity increased by 35%. There was no significant change in Vo2max or any of the other variables examined before and after training, and the patients with SBMA did not feel improvements in ADL.

Conclusions: Frequent, moderate-intensity aerobic conditioning is of little beneficial effect in patients with spinal and bulbar muscular atrophy (SBMA). High levels of plasma creatine kinase and muscle regeneration indicate a primary myopathic affection, which, in parallel with the motor neuron deficiency, may attenuate the response to exercise training in patients with SBMA.

Summary

Spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. To characterize the natural history and define outcome measures for clinical trials, we assessed the clinical history, laboratory findings and muscle strength and function in 57 patients with genetically confirmed disease. We also administered self-assessment questionnaires for activities of daily living, quality of life and erectile function. We found an average delay of over 5 years from onset of weakness to diagnosis. Muscle strength and function correlated directly with serum testosterone levels and inversely with CAG repeat length, age and duration of weakness. Motor unit number estimation was decreased by about half compared to healthy controls. Sensory nerve action potentials were reduced in nearly all subjects. Quantitative muscle assessment and timed 2 min walk may be useful as meaningful indicators of disease status. The direct correlation of testosterone levels with muscle strength indicates that androgens may have a positive effect on muscle function in spinal and bulbar muscular atrophy patients, in addition to the toxic effects described in animal models.